Kurzfassung

Molecular evolution and progression of liver cancer: from tumor-prevention to therapeutic approaches:
Liver carcinogenesis is a multi-stage process starting from pre-neoplastic dysplastic lesions that develop in chronically inflamed livers and evolve into early hepatocellular carcinoma (HCC) that progresses to advanced HCCs. Despite recent technological advancements, our knowledge of the molecular complexity and intra-tumoral heterogeneity in HCC is limited and a detailed catalogue of...Molecular evolution and progression of liver cancer: from tumor-prevention to therapeutic approaches:
Liver carcinogenesis is a multi-stage process starting from pre-neoplastic dysplastic lesions that develop in chronically inflamed livers and evolve into early hepatocellular carcinoma (HCC) that progresses to advanced HCCs. Despite recent technological advancements, our knowledge of the molecular complexity and intra-tumoral heterogeneity in HCC is limited and a detailed catalogue of (epi-)genetic alterations that promote hepatocarcinogenesis remains to be defined. This lack of information represents a major challenge for both, preventive strategies as well as therapeutic approaches in HCC. Our recent analyses indicate that early lesions show a surprisingly homogenous expression pattern which complicates accurate prediction of which lesions are at risk for malignant transformation. We further identified IGFALS (Insulin-like growth factor binding protein, acid labile subunit) as a major genetic determinant of progression in HCC associated with activation of distinct prognostic adverse signaling pathways. These observations highlight the importance of preventive therapeutic interventions at pre-neoplastic stages to effectively prevent tumor development. These observations also emphasize that the molecular heterogeneity and lack of clear oncogene addiction in advanced HCCs contribute to the disappointing response to standard therapies and the requirement for individualized treatment strategies. The goal of our project is to define the multi-stage molecular evolution of HCC (Figure 2). Since chronic inflammatory and structural alterations in the hepatic microenvironment usually precede hepatocarcinogenesis we will first test the impact of preventive modulation of the tissue milieu that promotes liver cancer development. Therefore, inhibition of key pro-oncogenic factors such as insulin signaling, inflammation as well as stem cell activation will be performed in mouse models both prior to and following induction of liver cancer. Further, the relevance of IGFALS for tumor-initiation and progression will be evaluated in vivo by using hydrodynamic injection. Next, we aim to characterize the sequential epigenetic evolution of liver cancer by applying whole epigenome sequencing to the complete spectrum of early and advanced lesions to create a detailed landscape of epigenetic alterations in hepatocarcinogenesis. We will then prospectively define the mutational landscape of human HCCs and assess the most abundant genetic alterations by a target next-generation sequencing approach. A particular emphasis will be placed on potentially drugable targets with the overall aim to identify novel therapeutic strategies. Finally, we will implement the obtained results to unravel key mechanisms responsible for chemoresistance by using the ex-vivo precision-cut liver slice tool as well as freshly isolated liver cancer cells.  
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